The role of senescent cells in ageing

Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013)

Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010)

López-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013)

Adams, P. D. Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Mol. Cell 36, 2–14 (2009)

Newgard, C. B. & Sharpless, N. E. Coming of age: molecular drivers of aging and therapeutic opportunities. J. Clin. Invest. 123, 946–950 (2013)

Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013)

Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961)A pioneering study that introduced the term senescence to describe the phenomenon of permanent growth arrest of primary human cells after extensive serial passaging in culture.

Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998)

Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)The study that established the concept of oncogene-induced senescence.

Rajagopalan, S. & Long, E. O. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proc. Natl Acad. Sci. USA 109, 20596–20601 (2012)

Muñoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013)

Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013)References 10, 11, 12 are studies demonstrating that senescence has a central role in tissue remodelling during embryogenesis.

Jun, J. I. & Lau, L. F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nature Cell Biol. 12, 676–685 (2010)

Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008)References 14, 15 show that senescent cells that are produced after tissue damage act to curb fibrosis.

Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nature Cell Biol. 10, 825–836 (2008); corrigendum. 14, 649 (2012)A study that demonstrated a causal link between cellular senescence and age-related tissue deterioration, and the concept of assisted cycling.

Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011)A study showing that clearance of p16Ink4a-positive senescent cells can delay age-related degenerative pathologies in a progeroid mouse model.

Nardella, C., Clohessy, J. G., Alimonti, A. & Pandolfi, P. P. Pro-senescence therapy for cancer treatment. Nature Rev. Cancer 11, 503–511 (2011)

Sedelnikova, O. A. et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nature Cell Biol. 6, 168–170 (2004)

von Zglinicki, T. Oxidative stress shortens telomeres. Trends Biochem. Sci. 27, 339–344 (2002)

Aird, K. M. et al. Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence. Cell Rep. 3, 1252–1265 (2013)

Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006)

Lazzerini Denchi, E., Attwooll, C., Pasini, D. & Helin, K. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol. Cell. Biol. 25, 2660–2672 (2005)

Kaplon, J. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013)

Kondoh, H. et al. Glycolytic enzymes can modulate cellular life span. Cancer Res. 65, 177–185 (2005)

Dörr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013)References 20, 23, 25 revealed that metabolic mechanisms are causally implicated in the induction and maintenance of the senescent state.

Shamma, A. et al. Rb Regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-ras isoprenylation. Cancer Cell 15, 255–269 (2009)

Ben-Porath, I. & Weinberg, R. A. The signals and pathways activating cellular senescence. Int. J. Biochem. Cell Biol. 37, 961–976 (2005)

Moiseeva, O., Mallette, F. A., Mukhopadhyay, U. K., Moores, A. & Ferbeyre, G. DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol. Biol. Cell 17, 1583–1592 (2006)

Romanov, V. S. et al. p21(Waf1) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate. Cell Cycle 9, 3945–3955 (2010)

Lapak, K. M. & Burd, C. E. The molecular balancing act of p16INK4a in cancer and aging. Mol. Cancer Res. 167–183 (2014)

Hein, N. et al. in Senescence (ed. Nagata, T. ) Ch. 9,. 171–208 (2012)

Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nature Genet. 36, 744–749 (2004)

Schmidt, S. et al. The centrosome and mitotic spindle apparatus in cancer and senescence. Cell Cycle 9, 4469–4473 (2010)

Freund, A., Patil, C. K. & Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 30, 1536–1548 (2011)

Passos, J. F. et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 6, 347 (2010)

Baker, D. J., Weaver, R. L. & van Deursen, J. M. p21 both attenuates and drives senescence and aging in BubR1 progeroid mice. Cell Rep. 3, 1164–1174 (2013)

Grove, G. L. & Cristofalo, V. J. Characterization of the cell cycle of cultured human diploid cells: effects of aging and hydrocortisone. J. Cell. Physiol. 90, 415–422 (1977)

Choudhury, A. R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genet. 39, 99–105 (2007)

Siegel, J. J. & Amon, A. New insights into the troubles of aneuploidy. Annu. Rev. Cell Dev. Biol. 28, 189–214 (2012)

Vredeveld, L. C. et al. Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes Dev. 26, 1055–1069 (2012)

Lapasset, L. et al. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev. 25, 2248–2253 (2011)

De Cecco, M. et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12, 247–256 (2013)

Wang, J. et al. Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human adult stem cells reinstates self-renewal. Cell Cycle 10, 3016–3030 (2011)

Ivanov, A. et al. Lysosome-mediated processing of chromatin in senescence. J. Cell Biol. 202, 129–143 (2013)

Purvis, J. E. et al. p53 dynamics control cell fate. Science 336, 1440–1444 (2012)

Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012)

Shimi, T. et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 25, 2579–2593 (2011)

Shah, P. P. et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 27, 1787–1799 (2013)

Funayama, R., Saito, M., Tanobe, H. & Ishikawa, F. Loss of linker histone H1 in cellular senescence. J. Cell Biol. 175, 869–880 (2006)

Narita, M. et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 126, 503–514 (2006)

Zhang, R., Chen, W. & Adams, P. D. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol. Cell. Biol. 27, 2343–2358 (2007)

Swanson, E. C., Manning, B., Zhang, H. & Lawrence, J. B. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J. Cell Biol. 929–942 (2013)

Shelton, D. N., Chang, E., Whittier, P. S., Choi, D. & Funk, W. D. Microarray analysis of replicative senescence. Curr. Biol. 9, 939–945 (1999)

Zhang, H., Pan, K. H. & Cohen, S. N. Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci. Proc. Natl Acad. Sci. USA 100, 3251–3256 (2003)

Coppé, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, e301 (2008)

Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature Cell Biol. 11, 973–979 (2009); erratum. 11, 1272 (2009)

Kuilman, T. & Peeper, D. S. Senescence-messaging secretome: SMS-ing cellular stress. Nature Rev. Cancer 9, 81–94 (2009)

Coppé, J. P. et al. Tumor suppressor and aging biomarker p16INK4a induces cellular senescence without the associated inflammatory secretory phenotype. J. Biol. Chem. 286, 36396–36403 (2011)

Coppé, J. P., Kauser, K., Campisi, J. & Beausejour, C. M. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J. Biol. Chem. 281, 29568–29574 (2006)

Freund, A., Orjalo, A. V., Desprez, P. Y. & Campisi, J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16, 238–246 (2010)

Laberge, R. M., Awad, P., Campisi, J. & Desprez, P. Y. Epithelial-mesenchymal transition induced by senescent fibroblasts. Cancer Microenviron. 5, 39–44 (2012)

Binet, R. et al. WNT16B is a new marker of cellular senescence that regulates p53 activity and the phosphoinositide 3-kinase/AKT pathway. Cancer Res. 69, 9183–9191 (2009)

Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008)

Yang, G. et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl Acad. Sci. USA 103, 16472–16477 (2006)

Benz, G., Holzel, D. & Schmoeckel, C. Inflammatory cellular infiltrates in melanocytic nevi. Am. J. Dermatopathol. 13, 538–542 (1991)

Finkel, T., Serrano, M. & Blasco, M. A. The common biology of cancer and ageing. Nature 448, 767–774 (2007)

Matheu, A. et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375–379 (2007)

Baker, D. J. et al. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nature Cell Biol. 15, 96–102 (2013)

Jun, J. I. & Lau, L. F. Cellular senescence controls fibrosis in wound healing. Aging 2, 627–631 (2010)

Wang, J., Geiger, H. & Rudolph, K. L. Immunoaging induced by hematopoietic stem cell aging. Curr. Opin. Immunol. 23, 532–536 (2011)

Nikolich-Žugich, J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nature Rev. Immunol. 8, 512–522 (2008)

Roninson, I. B. Tumor cell senescence in cancer treatment. Cancer Res. 63, 2705–2715 (2003)

Le, O. N. et al. Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell 9, 398–409 (2010)

Allan, J. M. & Travis, L. B. Mechanisms of therapy-related carcinogenesis. Nature Rev. Cancer 5, 943–955 (2005)

Jurk, D. et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11, 996–1004 (2012)A study showing that post-mitotic cells can obtain several key characteristics of senescent cells.

Minamino, T. et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nature Med. 15, 1082–1087 (2009)

Herbig, U., Ferreira, M., Condel, L., Carey, D. & Sedivy, J. M. Cellular senescence in aging primates. Science 311, 1257 (2006)

Lawless, C. et al. Quantitative assessment of markers for cell senescence. Exp. Gerontol. 45, 772–778 (2010)

Wang, C. et al. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8, 311–323 (2009)

Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006)

Jeyapalan, J. C., Ferreira, M., Sedivy, J. M. & Herbig, U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech. Ageing Dev. 128, 36–44 (2007)

Naylor, R. M., Baker, D. J. & van Deursen, J. M. Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin. Pharmacol. Ther. 93, 105–116 (2013)

Sherr, C. J. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res. 60, 3689–3695 (2000)

Campisi, J. Cellular senescence: putting the paradoxes in perspective. Curr. Opin. Genet. Dev. 21, 107–112 (2011)

Coppé, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010)

Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011)

Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007)

Krtolica, A. et al. GROα regulates human embryonic stem cell self-renewal or adoption of a neuronal fate. Differentiation 81, 222–232 (2011)

Pricola, K. L., Kuhn, N. Z., Haleem-Smith, H., Song, Y. & Tuan, R. S. Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. J. Cell. Biochem. 108, 577–588 (2009)

Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005)

Parrinello, S., Coppe, J. P., Krtolica, A. & Campisi, J. Stromal–epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci. 118, 485–496 (2005)

Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biol. 15, 978–990 (2013)

Nelson, G. et al. A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11, 345–349 (2012)References 92, 94 show that senescent cells can induce senescence in neighbouring cells through paracrine mechanisms.

Faggioli, F., Wang, T., Vijg, J. & Montagna, C. Chromosome-specific accumulation of aneuploidy in the aging mouse brain. Hum. Mol. Genet. 21, 5246–5253 (2012)

Garinis, G. A., van der Horst, G. T., Vijg, J. & Hoeijmakers, J. H. DNA damage and ageing: new-age ideas for an age-old problem. Nature Cell Biol. 10, 1241–1247 (2008)

Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007)

Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011)

Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004)

Bhaumik, D. et al. MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging 1, 402–411 (2009)